Cardiovascular disease, metabolic syndrome, microbes and metabolites in FHS

FHS 中的心血管疾病、代谢综合征、微生物和代谢物

• 批准号: 10556439
• 负责人: Ramnik J Xavier
• 金额: $ 95.59万
• 依托单位: BROAD INSTITUTE, INC.
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-02-01 至 2026-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10556439
• 关键词: Adrenal Cortex Hormones; Affect; Atherosclerosis; Bacteria; Biochemistry; Bioinformatics; Biological Assay; Biological Availability; Biology; Cardiometabolic Disease; Cardiovascular Diseases; Cardiovascular system; Cells; Cholesterol; Cholesterol Homeostasis; Circulation; Clinical; Clinical Data; Cohort Studies; Coupled; Coupling; Data; Data Set; Disease; Engineering; Enzymes; Epithelial Cells; Feces; Framingham Heart Study; Generations; Genes; Genetic Transcription; Gnotobiotic; Goals; Health; Human; Immune; In Vitro; Inflammation; Intestines; Investigation; Libraries; Link; Lipids; Liver; Measures; Medical; Metabolic; Metabolic Diseases; Metabolic syndrome; Metabolism; Metagenomics; Microbe; Microbiology; Mus; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Paper; Participant; Pathway interactions; Persons; Phenotype; Phytosterols; Plants; Process; Production; Proteins; Proteomics; Publishing; Risk Factors; Sampling; Serum; Steroids; Sterols; Structure; Substrate Specificity; System; Work; absorption; cardiometabolic risk; cardiovascular disorder risk; cardiovascular health; cholesterol dehydrogenase; cholesterol transporters; cohort; commensal microbes; cytokine; disorder risk; enzyme activity; gut bacteria; gut microbes; gut microbiome; gut microbiota; host-microbe interactions; human disease; intestinal epithelium; member; metabolomics; metagenomic sequencing; microbial; microbial community; microbiome; novel; reconstitution; transcriptomics

Cardiometabolic diseases affect millions of people worldwide and have numerous underlying risk factors. Commensal microbes that comprise the intestinal microbiome are implicated in the progression and onset of many of these diseases, including type 2 diabetes, obesity, and atherosclerosis. Gut microbes have extensive metabolic capabilities, allowing them to produce or modify molecules that influence disease risk. Members of the gut microbiota have been known to convert cholesterol into the poorly absorbable metabolite coprostanol for almost 100 years, however the microbial genes responsible for this metabolism were not known. In recent work, we analyzed paired gut metagenomic and metabolomic data to identify a novel group of cholesterol dehydrogenases that metabolize cholesterol when expressed in vitro. Using clinical and metagenomic data from the Framingham Heart Study (FHS), we observed lower serum cholesterol in subjects whose microbiomes encode these cholesterol dehydrogenases. The cholesterol dehydrogenases we originally described convert cholesterol to cholestenone and coprostanone to coprostanol, and we have since identified the intermediate enzyme that converts cholestenone to coprostanone. In this proposal, we will functionally characterize metabolism of sterols in the gut and determine the impact of this process on cardiometabolic disease. In Aim 1, we will identify determinants of host-microbe interactions by collecting and analyzing clinical variables with stool and serum samples from the Gen3/Omni2 FHS cohorts. We will generate coupled stool and serum metabolomics and metagenomics datasets, perform culturomics to assemble a microbial strain library, and identify host exposomes from clinical data. We will then utilize these data to identify and prioritize microbially- derived or modified circulating metabolites associated with CVD for further mechanistic investigations. In Aim 2, We will couple bioinformatics with microbiology and biochemistry for targeted identification of enzymes/proteins that alter sterol structures. This effort will allow us to probe the diversity of gut microbial sterol metabolizing enzymes and their substrates in order to determine specific microbes and genes with the capacity to modify cholesterol. Taking a systems-level approach, we will colonize mice with cholesterol-metabolizing microbial communities to determine how microbial metabolism modulates serum cholesterol and pathways central to cardiovascular disease. In Aim 3, we will functionally link microbiome enzyme activity to sterol metabolism and metabolic disease. We will employ cell-based transcriptional and proteomic assays to interrogate the effects of microbially-modified sterols on local sterol sensing pathways in epithelial cells and measure the effects of circulating sterol metabolites on human immune cells.

心脏代谢疾病会影响全球数百万的人，并具有许多潜在的危险因素。包含肠道微生物组的共生微生物与许多这些疾病的进展和发作有关，包括2型糖尿病，肥胖和动脉粥样硬化。肠道微生物具有广泛的代谢能力，使它们能够产生或修改影响疾病风险的分子。已知肠道微生物群的成员将胆固醇转化为近100年的可吸收代谢产物coprostanol，但是导致这种代谢的微生物基因尚不清楚。在最近的工作中，我们分析了配对的肠道基因组和代谢组数据，以识别一组新型的胆固醇脱氢酶，该胆固醇脱氢酶在体外表达时代谢胆固醇。使用Framingham心脏研究（FHS）的临床和元基因组数据，我们观察到微生物组编码这些胆固醇脱氢酶的受试者中血清胆固醇较低。我们最初描述的胆固醇脱氢酶将胆固醇转化为胆固醇和果仁烷酮，从而将胆固醇转化为coprostanol，此后我们已经鉴定出将胆固醇转化为促脂蛋白的中间酶。在此提案中，我们将在肠道中功能表征固醇的代谢，并确定该过程对心脏代谢疾病的影响。在AIM 1中，我们将通过从GEN3/OMNI2 FHS队列中收集和分析粪便和血清样品来确定宿主 - 微生物相互作用的决定因素。我们将生成耦合的粪便和血清代谢组学和宏基因组学数据集，执行培养物来组装微生物菌株库，并从临床数据中识别宿主的外汇体。然后，我们将利用这些数据来识别并确定与CVD相关的微生物衍生或修改的循环代谢物进行进一步的机械研究。在AIM 2中，我们将生物信息学与微生物学和生物化学相结合，以靶向改变固醇结构的酶/蛋白质。这项工作将使我们能够探测肠道微生物固醇代谢酶及其底物的多样性，以确定具有修饰胆固醇的能力的特定微生物和基因。采用系统级方法，我们将用胆固醇代谢的微生物群落定居小鼠，以确定微生物代谢如何调节血清胆固醇和心血管疾病中心的途径。在AIM 3中，我们将在功能上将微生物组活性与固醇代谢和代谢疾病联系起来。我们将利用基于细胞的转录和蛋白质组学测定法来询问微生物修饰的固醇对上皮细胞中局部固醇传感途径的影响，并测量循环固醇代谢物对人免疫细胞的影响。